1. Field of the Invention
The present invention relates generally to the fields of molecular biology, pharmaceuticals, and medicine. More particularly, it concerns Skp2 inhibitors.
2. Description of Related Art
Cancer is a complex disease characterized by multiple steps of genetic alterations occurring primarily through mutations of tumor suppressors and oncogenes. To date, chemotherapy and radiotherapy represent two major options for cancer treatment through inducing p53-dependent cellular senescence and apoptosis (Mandinova and Lee, 2011; Vazquez et al., 2008). However, advanced cancers often develop resistance to these treatments as they had often lost the p53 response due to frequent mutations on the p53 gene (accounting for ˜50% in cancers). In this scenario, developing novel cancer treatment strategies via boosting p53-independent senescence and/or apoptosis responses is a key to the success of advanced cancer treatments.
In addition to activating senescence and apoptosis for cancer treatment, targeting aerobic glycolysis, a phenomenon called the Warburg effect (Vander Heiden et al., 2009; Warburg, 1956), has recently emerged as a promising strategy for cancer therapies. Cancer cells can display elevated glycolyis irrespectively of the presence or absence of oxygen, which warrants cancer cell proliferation and survival. Aerobic glycolysis is affected by oncogenic Akt kinase, a master kinase regulating many biological processes by phosphorylating its substrates (Buzzai et al., 2005; Elstrom et al., 2004; Robey and Hay, 2009). Activation of Akt is achieved by engaging growth factors to their cognate receptors. It has been recently discovered that Akt undergoes non-proteolytic K63-linked ubiquitination by TRAF6 E3 ligase upon IGF-1 treatment, which plays a critical role for Akt membrane recruitment, phosphorylation, and activation (Yang et al., 2009). Thus, K63-linked ubiquitination of Akt represents a posttranslational modification critical for Akt membrane recruitment and activation. Interestingly, Akt ubiquitination is also induced by activation of ErbB family receptors. Surprisingly, Skp2 SCF complex, but not TRAF6, is found to be critical for EGF-mediated Akt ubiquitination, phosphorylation, and activation (Chan et al., 2012). Thus, distinct E3 ligases are utilized to trigger Akt ubiquitination and activation by various growth factors.
Skp2 is an F-box protein, constituting one of the four subunits of the Skp1-Cullin-1 (Cul-1)-F-Box (SCF) ubiquitin E3 ligase complex. Earlier studies showed that Skp2 regulates apoptosis, cell cycle progression and proliferation by promoting ubiquitination and degradation of its substrates such as cell cycle inhibitor p27 (Nakayama et al., 2000; Nakayama et al., 2004). However, a new role of Skp2 SCF complex has been attributed in triggering non-proteolytic K63-linked ubiquitination (Chan et al., 2012). Overexpression of Skp2 is frequently observed in human cancer, and is inversely correlated with p27 levels, suggesting that Skp2 overexpression may have essential functions in human cancer development as a result of p27 downregulation (Hershko, 2008). In line with these observations, overexpression of Skp2 in prostate cancer cells significantly promotes tumorigenesis in a xenograft tumor model (Lin et al., 2009). Moreover, Skp2 overexpression has been found to promote cancer invasion and metastasis, whereas its deficiency inhibits these processes (Chan et al., 2010a). Using a Skp2-deficient mouse model, it has been shown that that Skp2 is required for cancer development in multiple tumor-promoting conditions, including PTEN, ARF, pRB inactivation as well as Her2/Neu overexpression. This may be achieved by triggering p53 independent, p27-dependent cellular senescence/apoptosis or inhibiting Akt-mediated glycolysis (Chan et al., 2012; Lin et al., 2010; Wang et al., 2010). Collectively, these studies suggest Skp2 targeting is a promising strategy for cancer treatment, thereby calling for an urgent need to develop specific Skp2 inhibitors.